"Cognition” has more than one meaning. Cognitive-behavioral therapy refers to therapies that work on changing automatic thoughts and resulting schemas. When effective, cognitive therapy helps patients:

• Become aware of automatic thoughts

• Appreciate how these lead to schemas that distort global perception and limit one’s repertoire of responses

A common metaphor for successful cognitive-behavioral therapy is that a patient comes in seeing the glass as “half empty” and leaves able to see that even “half-empty” glasses are simultaneously “half-full.”

In contrast, cognitive remediation, developed by neuropsychologists who initially used techniques for helping persons with traumatic brain injury, uses exercises—many computer-based—and other techniques to help patients with deficits in underlying processes that lead to disruptions in thinking. Cognitive remediation is focused not on distortions in global schemas but on neurocognitive processes that need to be either strengthened or bypassed by auxiliary pathways.

Pharmacotherapy for cognitive symptoms uses medications to correct dysfunctions in the processes that underlie thinking. Eventually, we will find ways to combine cognitive remediation with pharmacological interventions in treating cognitive symptoms in schizophrenia and other neuropsychiatric disorders.

An excellent operational definition for cognition as conceptualized in this article is that of Medalia and Revheim,1 2 leaders in the field of cognitive remediation. “Cognition refers to thinking skills, the intellectual skills that allow you to perceive, acquire, understand and respond to information. This includes the abilities to pay attention, remember, process information, solve problems, organize and reorganize information, communicate and act on information.”1(p5)

During the 1970s and 1980s, empirical work led researchers to propose that schizophrenia be seen as a disorder comprising more than one underlying process.2-4 In the 1990s, as pharmaceutical companies began marketing atypical antipsychotics as agents that improved negative as well as positive symptoms in addition to having fewer motor adverse effects, the concept of schizophrenia as a multidimensional disorder became widely accepted.5

Assessing cognition

Large-scale pharmaceutical company studies, along with investigator-initiated studies they inspired, frequently used 1 or more of the following symptom severity rating scales:

• The Scale for the Assessment of Negative Symptoms (SANS)6

• The Scale for the Assessment of Positive Symptoms (SAPS)7

• The Positive and Negative Syndrome Scale (PANSS)8

Large-scale studies provided data for SANS/SAPS and the PANSS-rated symptoms, which led to the approval of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole and allowed for factor analysis.

Factor analysis of the SANS/SAPS ratings revealed 3 factors: positive, negative, and disorganized symptoms. Factor analysis of the PANSS-rated symptoms revealed 5 factors: positive, negative, dysphoric mood, excitement/hostility (sometimes called activation), and cognitive (sometimes called autistic preoccupation) symptoms. For both SANS and SAPS, poor performance on neuropsychological tests was found to correlate with the negative and disorganized factors. Negative symptoms were related to poor performance on tests of verbal learning and memory, verbal fluency, visual memory, and visual-motor sequencing, while disorganized symptoms were correlated with lower verbal IQ and poor concept attainment.9

For the PANSS, poor performance on neuropsychological tests was found to correlate with the negative and the cognitive/autistic preoccupation factors, but not with severity of positive symptoms. In a study by Opler and colleagues,10 PANSS negative symptoms were found to be associated with difficulties in performing the Wisconsin Card Sorting Test (WCST), a measure of executive functioning and prefrontal integrity. Bell and colleagues11 found that the PANSS cognitive factor significantly correlated with poorer performance on all neuropsychological tests in a comprehensive battery that included the WCST.

Clearly, important questions remain to be answered about whether neurocognitive deficits are best conceptualized as correlates of negative and disorganized symptoms or whether they are a distinct independent feature. To the extent that neurocognitive deficits correlate with negative and disorganized symptoms, we also need to better understand how they are underlying contributors to these symptom dimensions.

The NIMH’s initiative, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), has jump-started the process for treating cognitive deficits in patients with schizophrenia. It has brought together experts and developed a consensus battery to be used by the FDA, and presumably other regulatory agencies, to evaluate the efficacy of new medications for the treatment of cognitive symptoms in schizophrenia.12 As shown in the Table, the resulting MATRICS Consensus Cognitive Battery consists of 10 tests that assess 7 cognitive domains.13

The role of neurochemical systems

Three neurochemical systems have emerged as potential targets for pharmacological agents: the cholinergic, D1 dopamine, and N–methyl D–aspartate (NMDA) glutamate systems. While not the only systems suggested and worthy of investigation, the consensus appears to be that these 3 offer the most promise.

In discussing these systems, rather than cataloguing ongoing or recently completed clinical trials, I focus on ways that practicing clinicians can begin to target these systems. Since there are no FDA-approved medications for the treatment of cognitive symptoms in schizophrenia, any suggested use of a presently available medication for treating cognitive symptoms in schizophrenia is by definition an off-label use. The off-label use of medications approved for other purposes is appropriate but needs to be evidence-based, discussed with the patient, and the best alternative.

Pharmacotherapy should be used with other psychosocial interventions. In the case of cognitive symptoms, combining pharmacotherapy with cognitive remediation, in addition to more traditional approaches, may lead to better quality of life and more rapid recovery.

The cholinergic system

In the 1970s, it was found that Alzheimer disease was caused primarily by the degeneration of acetylcholine (ACH) or cholinergic neurons that emanate from the nucleus basalis of Meynert. This landmark finding was on the one hand startling, since it had been thought that more widespread neurochemical deficits would be found. On the other hand, it was consistent with decades of work that showed that anticholinergic medications disrupted cognitive functions and, in particular, memory in nonpatient populations. Regarding schizophrenia, a small but compelling literature indicates that anticholinergics counter the therapeutic action of neuroleptics.14 Findings from recent clinical trials indicate that both muscarinic and nicotinic agonists hold promise in the treatment of cognitive symptoms of schizophrenia.15-16